Executive functions are vulnerable to alcohol intoxication as it interferes with goal-directed behavior, ability to evaluate conflicting demands, inhibit impulsive responses, and optimize behavior. These impairments may result in a decreased capacity to exert self-restraint, contributing to increased drinking and dependence. Patterns of alcohol consumption and the risk for dependence are characterized by inter individual variability as the environment interacts with genetic susceptibility such as family history of alcoholism. Dopaminergic (DA) system mediates development and maintenance of addictive behaviors via reward regulation. However, the neurofunctional basis of DA-ergic influence on the top-down regulatory influence and its interaction with alcohol and impulsivity traits is poorly understood. The overall goal of this project is to use the multimodal imaging to examine the neurobiological basis of gene x environment interactions in the population at risk during inhibitory control and alcohol challenge. Its design includes well-defined functional polymorphisms regulating DA and GABA that are relevant to inhibitory control and alcoholism. The proposed paradigms recruit prefrontal circuitry shown to be sensitive to genotypes of interest in our preliminary investigations. Our multimodal approach comprises functional magnetic resonance imaging (fMRI) that provides spatial maps of activity related to conflict-inducing tasks, whereas the excellent temporal resolution of magneto- and encephalography (MEG/EEG) elucidates the timing and the oscillatory dynamics of alcohol-related abnormalities. Converging with our fMRI studies, the anatomically-constrained MEG approach indicates that the anterior cingulate cortex (ACC) is especially vulnerable to alcohol effects during conflict processing. Alcohol attenuates theta oscillations estimated to the ACC. Furthermore, oscillatory synchrony between the ACC and lateral prefrontal cortex (PFC) is dysregulated by alcohol, possibly underlying impaired inhibitory control. Our preliminary data indicate that the prefrontal neurofunctional systems underlying decision making, response inhibition, and error processing are differentially associated with the functional COMT Val158Met polymorphism during intoxication. Given these interactive contributions, we propose to obtain a rich set of complementary measures in individuals with a positive vs. negative family history of alcoholism. Behavioral and multimodal neuroimaging measures of inhibitory control and novelty processing will be obtained during alcohol challenge and will be analyzed as a function of genetic markers relevant to DA and GABA signaling and dispositional traits. The confluence of information will be analyzed separately and in synergy and will provide multidimensional insight into the basic mechanisms underlying alcohol-induced impairment of inhibitory control in real time as a function of family history and genetic makeup, with implications for individualized prevention strategies and pharmacogenetics.